We propose that the role played by mononuclear phagocytes (MP; microglia, perivascular and brain macrophage) in the neuropathogenesis of H1V-1 infection can be harnessed for therapeutic benefit. The work will be conducted in the Department of Pharmacology and Experimental Neuroscience at the University of Nebraska Medical Center (UNMC). The department is a result of the merger of the Center of Neurovirology and Neurodegenerative Disorders (CNND) and the UNMC Department of Pharmacology. The fusion of the two created a Neuroscience Program with one director, Howard E. Gendelman, significantly improved the program project scientific infrastructure. Indeed, the disciplines of neuroscience, immunology, and pharmacology are integrated as a result of the CNND's evolution since its formation in 1997. Ongoing collaborations in stem cell biology, neuropharmacology, virology, blood-brain barrier biology, proteomics, bioimaging, and molecular neuroscience are now operative and an integral part of this proposal. Links between intracellular processes, microglial activation, and neuronal degeneration provided opportunities to harness immune responses for therapeutic benefit. The proposal includes three projects that center around MP pathobiology including: neural progenitor stem cell mobility and function in laboratory and animal models of NeuroAIDS (project, 1, J. Zheng); a blood-borne monocyte derived-macrophage-based nanoparticle delivery of anti-retroviral drugs in NeuroAIDS (project 2, H. Gendelman); and studies of the molecular, biochemical, and cell biologic consequences to the blood-brain barrier and viral neuropathogenesis in laboratory and animal models of human disease (project 3, Y. Persidsky). The cores include: cell biology and brain tissue collections (core A, T. Ikezu), bioimaging (core B, M. Boska), proteomics (core C, P. Ciborowski), and an administrative oversight (core D, H. Gendelman). Each project/core will support, enhance, and provide interdisciplinary research that will enhance the quality of the works and the opportunities for cross-validation of experimental results and success. Taken together, the program has matured, is focused, productive, and synergistic. All the resources, techniques, and models are in place to permit the necessary opportunities for significant contributions to the field.